Influence of sexually transmitted infections on the cervical cytological abnormalities among Iranian women: A cross-sectional study

Abstract Background Sexually transmitted infections (STIs) are one of the world's most severe health challenges. The existence of STIs such as human papillomavirus (HPV) might cause cervical cell changes leading to cervical cancer. Objective This study aims to assess the association of STIs with cervical cytological abnormalities and genital warts among women in northeastern Iran. Materials and Methods This cross-sectional study was carried out on 190 women referred to the central laboratory of Academic Center for Education, Culture, and Research, Mashhad, Iran from March to July 2022. The presence of genital infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Herpes simplex viruses (1 and 2) were assessed using the real-time polymerase chain reaction method. HPV genital infection was detected based on the principles of reverse hybridization, and cellular changes in the cervix were examined by the liquid-based cytology technique. Results The mean age of participants was 35.33 ± 8.9 yr. 34 different HPV genotypes were detected in all HPV-positive cases, and the most common genotype was low-risk HPV6. No significant association was found between STIs and cervical cytology abnormalities. The prevalence rates of sexually transmitted pathogens among HPV-positive and HPV-negative individuals were 10.9 and 1.6%, respectively. The frequency of genital warts was significantly higher in cases with multiple infections of high- and low-risk HPV genotypes. Conclusion High percentages of the participants with non-HPV STIs and HPV infection had normal cervical cytology. It is advised to use STIs and HPV diagnostic tests along with cytology examinations for cervical cancer screening.


Introduction
Sexually transmitted infections (STIs) are considered a global health problem (1) (2). More than 1 million people are infected with STIs per day (3).
Most STIs infection are asymptomatic and can lead to various outcomes, such as pelvic inflammatory disease, sterility, ectopic pregnancy, congenital infections, and cervical cancer (4). The presence of some STIs facilitates the transmission of other infections and can cause cellular changes that precede some types of cancer (5). Cervical cancer has been one of the most common cancers among females and the 4 th most common type after breast, colorectal, and lung cancers. It was shown that an important cause of cervical cancer is HPV (6).
HPV is one of the most frequent STIs and is normally transmitted through direct contact with infected skin or mucosa (7). Depending on their oncogenic potential, HPV is divided into highrisk (HR) and low-risk (LR) groups. This should be mentioned that the HPV infection is effective risk factor for cervical cancer but it is not enough cause of cancer (8). Most HPV infections are temporary; however, a few cases of infections continue and progress to HR lesions and cancer.
Some STIs agents such as N. gonorrhoeae and Mycoplasma genitalium (M. genitalium) could change the genital tract flora through repeated infections and provoke cervical cancer. The increase in microbial species in genital tract causes an increase in cervical cancer (9,10      Binary logistic regression was used to evaluate the independent effects of smoking on HPV infection.

Statistical analysis
The statistical significance was set at p < 0.05.  (Table II). However, no significant association was observed between HPV infection and abnormality of cervical cytology. Moreover, no association was found between HPV genotypes (HR and LR) and abnormality of cervical cytology. In addition, STIs or co-infection of HPV and STIs had no significant relationship with an abnormality of cervical cytology (Table II).

Discussion
In the present study, 34 different HPV genotypes were detected in all HPV-positive women. The most common genotype was LR-HPV6 (26.6%). We This finding is consistent with another study that has recommended that HPV and non-HPV STIs are more prevalent in young women ≤ 25 yr of age (11). Perhaps immature cervical tissue and higher sexual activity make these women prone to the growth of pathogens (12). One of the cofactors associated with HPV infection is the age of the first sexual intercourse (11), but no significant difference showed the frequency of LR-HPV6 and HR-HPV16 to be 77 and 15%, respectively, as the most prevalent genotypes, while HPV-18 was not detected in their study (13).
In contrast to the present results, a study found that HR-HPV16 was the most prevalent genotype (49.2%) followed by HR-HPV18 (25.3%), while in the current work, the prevalence of HR-HPV18 was very low (2.3%) (2). In a previous study conducted by the authors, the LR-HPV6 was the most prevalent genotype (43.9%) and HR-HPV18 was not prevalent in comparison with other genotypes with a frequency of 17.7%, which is considerably higher than its prevalence in the current study.
This may be due to changes in the trend of prevalent genotypes in the region under study (14).
The frequency of multiple HPV-genotype infections was relatively high in the current study (46.87%).
One study showed that multiple HPV infections were associated with the occurrence of cytological abnormality (11), which is consistent with this study.
Moreover, a significantly higher prevalence of warts was found in participants with multiple HPV infections, and more cytological abnormalities were identified in participants with multiple HPV infections in this study, but they were not significant.
C. trachomatis may be a reason for female infertility and clinical manifestations (15). C.
trachomatis is a prevalent sexually transmitted bacterial infection (16). Nevertheless, the most In contrast to the results of another study, no significant association was found between HPV infection or STIs and cervical cytological abnormalities in the present study (2). In a study with similar results to the current study, no significant association was observed between HPV/STIs co-infection and the cervical abnormality (19).
In agreement with other studies, our results demonstrated an association between HPV infection and the incidence of warts.
We found LR-HPV6 to be the most common genotype among wart sufferers. In an investigation that had similar results to this work, they showed that LR-HPV6 was the most prevalent genotype in wart samples (36.3%) (20). In this research, it was revealed that multiple infections of HR and LR genotypes are more likely to cause warts, and warts are more common in people who have an LR-HPV genotype than in cases with HR-HPV.
Consistent with the current results, another study revealed that co-infection of both low-and HR-HPV types increases the risk of developing genital warts (OR: 2.814; 95%: 1.208-6.55, p = 0.017). Additionally, similar to the results of the present study, they found that LR-HPV genotypes have a higher risk of genital warts in comparison with HR-HPV types (21). The results of a study showed that the LR-HPV genotype was the major cause of genital warts and HR-HPV infections, and multiple HPV-type co-infections were also common in genital warts. Also, they found HPV6, 11, 52, and 16 as the 4 most common HPV types in genital warts (22). In the current study, HR-HPV16 was the 2 nd most prevalent genotype in participants with warts.
Similar to the present results, a study demonstrated that the most prevalent genotype was LR-HPV6 (47%), but unlike the current study, in which HR-HPV16 was detected as the 2 nd most prevalent cause of wart, they identified LR-HPV11 (13.6%) as the 2 nd most widespread genotype (23).
As revealed in another study as well as the present study, the risk of HPV infection increases in current smoker individuals in comparison with non-smokers. Similar to the findings of this research, they showed that the risk of HPV infection increases 1.9 times from smokers to non-smokers (OR = 1.905, CI 95% (1.426-2.545), p < 0.05) (24).

Conclusion
In conclusion, the current study has shown a high prevalence of LR-HPV6 in HPV-positive individuals as well as in cases with warts. It was found that smoking increases the risk of HPV infection. A high percentage of HPV-positive and STI-positive participants had normal Pap smear, so it seems that a Pap smear test alone is not enough for cervical cancer screening, and it is suggested to prepare HPV and non-HPV STI tests as well. According to the present results, higher prevalence rates of HPV and STI were found in women ≤ 25 yr of age, and it seems that a STI screening plan should be applied at this age.
The potential limitations of the current study were sampling method and small sample size. Since the number of participants with abnormal cytology was